Hope in the Pipeline I: New Tools for Recognizing TB (Dr. Mark Perkins)

8/7/2019 Hope in the Pipeline I: New Tools for Recognizing TB (Dr. Mark Perkins)

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Diagnostic testing for tuberculosis


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3 - 9 months


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The slow road to microscopy diagnosis ofTB

AFB/ml

Implement molecular test with

sensitivity similar to culture


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10,000,000

AFB/ml

Where delay contributes greatest to

morbidity, mortality, transmission

Abbreviating delay through better sensitivity or better access

AFB/ml

Implement dipstick with

sensitivity equal to microscopy

Implement molecular test with

sensitivity similar to culture


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Where is the point of care forTB and how do you get to it?

Reference center

District hospital

Microscopy center

Health post


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Referral for 3.8b people in 22 HBC

325

1500

27,000

270,000

1,52m?

Reference center

District hospital

Microscopy center

Health post


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Strength of

health system


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Simple one-step testing in 15 minutes

Accurate, quantitative readout

Simultaneous results from multiple markers

Portable, low maintenance instrument

Built-in quality control

Complex, slow tasks

Inaccurate, qualitative readout

Single marker, single disease

Heavy, high maintenance instruments

Absent quality control

Major Markets Rest ofWorld


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Liaise with funders, pharmaceutical

and biotech companies, research

institutions, academia

Create network of public and private partners

to create effective tests and demonstrate their

success

Liaise with funders, multi-lateral

agencies, NGOs,health ministries,

and agencies like GDF and

GFATM

Market accessand distribution

Discoveryand research

FINDs focusUpstream Downstream

Development EvaluationDemonstratio

n

Development

Facilitate,co-fund,

co-develop

Evaluation

Regulatory-quality

lab & fieldtrials

Demonstration

Large-scaleprojects

measuringfeasibility and

impact ondisease control

programs

Proof of

principle

Product

in box

Efficacy

Data

Effectiveness

DataPolicy

FIND: a public engine for diagnostic development


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Making US standard accessible in DEC

Price negotiations on MGITLicensing agreement for MPT64

Development for lower cost version

Large demonstration projects (>100,000 pts)

Customer support plan


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Steps in Hain test for molecular MDR screening

withPCR and line probe hybridization

Process specimen, extract

DNA, amplify DNA targets

withPCR

Hybridize amplified DNA

to oligonucleotide probes

on strips


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17 y.o. male

admitted to hospital

with

cough

and fever

AFB microscopy positive:

patient placed in isolation

pending drugsusceptibility testing

18th birthday

passed in

isolation

Conventional

DST results:

fully susceptible

0 10541 2 63 7 98 11 12

weeks

Geneva, Switzerland - 2007


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Evolution ofTB

diagnostics in

the publicsector

Fundamental

diagnostic: 1882

Fundamental

diagnostic: 2009


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Integrated NAAT forTB/Rif

XpertTMMTB/Rif

A technology platform for

TB & Rif resistance

TB Quinolone resistance

Potential for HIV viral load

Automated sample preparation

Amplification and detection

< 2 h

Workflow

fully automated, with 1-step external sample prep.

time-to-result < 2 h (walk away test)

throughput: up to 1-48 tests / run

no bio-safety cabinet

closed system (no contamination risk)


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Xpert MTB/Rif: FIND Evaluation studies

Rigorous performance evaluation at 5 sites (>1500 TB suspects)

Included 2 sites withhigh HIV prevalence (80%) & 2 withhigh MDR prevalence (>30%)

UCT SAMRC

HIV 77% 72%

TB (C+) 39% 13%

MDRTB 10% 9%

Hinduja

HIV 5%

TB (C+) 60%

MDRTB 67%

STI

HIV 5%

TB (C+) 42%

MDRTB 31%

UPCH

HIV 2%

TB (C+) 61%

MDRTB 7%


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Xpert MTB/Rif: FIND evaluation studies

Sensitivity forin S+/C+ = 100%,in S-/C+ = 91%

High accuracy forRif detection

Sequencing data for discrepant results suggest Xpert correct


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Closed system

IsothermalRapid

Multiprimer

Visible readout

Simple, manual NAAT


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TBLAMPProcedure

Sputum

85, 5 min

LAMP reation67 40 min

Calcein fluorescence

Dried

reagent

Mixing

Onedrop

Single instrument

From 32 to 7 steps

From 15 to 3 plastics


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Spiked sputum samples


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Decentralization of molecular diagnostics

2008 2010 2011 2015

LPA

1st generationMDR

LAMP

1st generationmanual detection

2nd generationmanual detection

POC testXpert

2nd generationautomated MDR


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Serodiagnosis ofTB


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Antigen Europe, HIV

(n=71)

Africa, HIV

(n=79)

Africa, HIV+

(n=77)

TB9.7 35% 79 % 91%

CFP10:ESAT6* 25% 64% 49%

TB10.2 21% 45% 48%

TB15.3 41% 75% 65%

TB16.3 55% 81% 88 %

TB 51 31% 76% 48%

TB51.7 57% 83% 78%

aCry:MPT83 26% 83% 58%

38 kDa 19% 29% 15%

Sensitivity of selected antigens at >95%

specificity level compared to healthy controls


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Whole proteome screening of

M. tuberculosis for diagnostic antigens


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Collaborations

Existing Assays: Chemogen, Inverness,Biomed, J Mitra, Lionex, SMI /TBDiaDirect, Standard, ANDA

Biomarkers: Forsythe, Harvard / BethIsrael, SSI, Proteome Systems, TAUNS,Cellzome, St. Georges Hospital,Genovac, Cornell, NYU, MPI / GC-6, KIT,Scensive, EMBO

Technology: SBRI, CibiTest, Nanogen,L

RE MedicalInverness, DKFZ,

Singulex,Chimera, deTect, Roche, Luminex,

ProteomeBinders, BD, Biomerieux,

Mtb Antigen DetectionAnother needle in the haystack?

Documents

Hope in the Pipeline I: New Tools for Recognizing TB (Dr. Mark Perkins)